Investigating age-dependent differences in cardiac drug response - Project Summary: Pediatric patients with congenital heart disease (CHD) frequently require pharmacological interventions (e.g., inotropic agents) to stabilize and improve cardiac mechanical function after corrective heart surgery. However, the medications administered to hospitalized children have not been formally studied in this population - due to underrepresentation of pediatric patients in clinical trials. Indeed, postnatal development is a dynamic process, as cardiomyocytes undergo significant adaptations in cell structure, calcium handling, and contractile function. We hypothesize that cardiomyocyte maturity strongly influences pharmacodynamics, and that consideration of age-specific differences in inotropic drug response can improve clinical care by tailoring drug therapies to pediatric patients. This proposal will investigate driving factors of postnatal cardiomyocyte maturation, the physiological effects on electrophysiology and contractility, and the impact on myocardial response to inotropic agents. Specifically, Aim 1 will investigate age-specific differences in drug response on cardiac electrophysiology and excitation- contraction coupling. A juvenile guinea pig model will be used to measure electrocardiograms, electrophysiology metrics, optical action potentials and intracellular calcium transients, and left ventricular pressure during baseline conditions and following treatment with calcium, dopamine, or milrinone. Tissue samples will be collected for mechanistic analysis of developmental changes in gene and protein expression. Aim 2 will investigate postnatal development of human cardiomyocytes and the impact of age on drug response. To aid in the translation of our animal studies, I will collect human cardiac tissue samples from neonates, infants, and children undergoing corrective heart surgery at my institution. Age-dependent changes in gene and protein expression will be quantified. Calcium transients will also be recorded from live, human heart tissue slice preparations under baseline conditions and in response to inotropes. By providing data on pediatric heart development and drug responsiveness, the results of this study will have a significant impact on the cardiac research field, cardiac surgery, and critical care medicine. Further, this 3-year training plan will support my scientific growth, which builds upon the expertise of my Sponsor (Dr. Posnack: cardiac electrophysiology, pharmacology) and co- Sponsor (Dr. Ishibashi: pediatric cardiac surgery). I will also benefit from interactions with collaborators and a mentoring team, who will provide guidance in career development, the goals of this study, and experimental techniques (e.g., optical mapping, molecular biology). This proposal will advance my knowledge in cardiac physiology, pharmacology, and clinically relevant approaches – and support my future goal of independently leading a translational cardiac research laboratory.
